The invention relates to a microdialysis device comprising at least a probe provided with an inlet and an outlet for bringing a perfusion fluid into contact with a bodily fluid in a part of a living organism and causing constituents from this fluid to be taken up by this perfusion fluid, whereby the perfusion fluid is enriched to dialysate.
Such a device is known from the U.S. Pat. No. 5,640,954. The device known from this patent relates to a method and a device for continuously monitoring the concentration of a metabolite, such as a glucose or lactic acid, in biological tissue, in which a perfusion fluid is guided to a microdialysis probe implanted in the subcutaneous tissue and is discharged therefrom as dialysate after enrichment with the metabolites from the tissue fluid. According to the described method an enzyme is added to the dialysate, and the concentration of the metabolite in the dialysate is determined under the selective effect of the enzyme at a measuring point ex vivo, making use of an electrochemical sensor.
It is a drawback of the known microdialysis device that for analysis of the constituents taken up in the perfusion fluid, although performed on-line, use is made of relatively voluminous conventional analytical equipment which limits the clinical application of the microdialysis technique. This analysis equipment must be connected using tubes and adaptors to the microdialysis probe, the flow rate of which is exceptionally small (in the order of magnitude of microlitres per minute). The resulting dead volume in combination with the extremely small samples for analysis represents a problem. It is further a drawback of the known device that connecting of the separate components thereof using hoses and coupling pieces does not preclude the possibility of errors being made by an operator. It is a further drawback that the known device is in principle suitable for performing an analysis of only a determined constituent, because the addition of enzyme makes the dialysate unsuitable for analysis of other constituents.
It is an object of the invention to provide a microdialysis device with which extremely small quantities of dialysate can be analysed in reliable manner with a negligible waiting time, wherein a plurality of constituents can be determined and wherein the possibility of an operator making errors is virtually precluded.
According to the invention a microdialysis device of the type stated in the preamble is proposed for this purpose, wherein the outlet of the probe is integrally received in a silicon chip and debouches in a first fluid channel formed in this silicon chip.
Such a device for microdialysis not only provides the advantage that the dead volume is significantly smaller than in a device according to the prior art, but also provides the possibility of integral arrangement in the silicon chip or in the housing thereof of vulnerable junctions in the fluid conduits to and from the probe.
In an advantageous embodiment of a microdialysis device according to the invention, which further comprises analysis means for analysing constituents of the bodily fluid taken up by the perfusion fluid, at least one analysis means is integrally received in the silicon chip in a manner such that dialysate flowing from the outlet comes into contact with this analysis means in the first fluid channel.
In one embodiment the at least one analysis means comprises a sensor, for instance an ion-sensitive field effect transistor (ISFET).
In a further embodiment the at least one analysis means comprises a fluid reservoir in the silicon chip, via which reservoir constituents from the dialysate come into contact with a sensor received in this reservoir, or which reservoir for instance contains a calibration fluid with constituents for adding to the dialysate in the first fluid channel.
The presence of particular substances in the dialysate and, in combination with a fluid reservoir containing a calibration substance, also the concentration of these determined substances is determined using a sensor.
The fluid reservoir is for instance separated by a semipermeable membrane from the first fluid channel, or for instance contains a gelled fluid, wherein the first fluid channel comprises a cavity formed in the gelled fluid.
In another embodiment the at least one analysis means comprises a fluid reservoir which is provided with a layered structure of a precious metal and a salt derived from that precious metal and which contains an electrolytic solution. A reference electrode integrated into the silicon chip is thus provided which can for instance be used as counter electrode of a sensor for a potentiometric measurement, for instance a pH measurement, of dialysate flowing through the fluid channel.
In yet another embodiment the silicon chip is provided with pumping means for pumping the perfusion fluid respectively the dialysate.
In an advantageous embodiment the pumping means are adapted for intermittent pumping of the perfusion fluid respectively the dialysate.
Intermittent pumping provides the option of holding the perfusion fluid in a probe introduced into a part of an organism at the same location for some time, until in an equilibrium situation constituents from the bodily fluid are taken up in the perfusion fluid, for instance by diffusion through a semi-permeable part of the probe at that location. The thus formed dialysate can subsequently be pumped to a sensor present in the silicon chip, where the dialysate can be kept in contact with this sensor for a chosen, sufficiently long period. This offers the advantage that sensors become available which would be unsuitable in the case of a measurement with non-intermittent pumping means due to these sensors having too long a response time.
The pumping means for instance comprise at least one closed reservoir which is filled with a reversibly expandable medium and is provided with an actuator for this medium, which reservoir is provided on one side with a movable wall part. When this movable wall part also forms part of a conduit for perfusion fluid or dialysate, the moving wall part, optionally in combination with suitably chosen and placed valves in this conduit, can be utilized for pumping the relevant fluid through this conduit.
The expandable medium expands in a physical or physical-chemical process, preferably in reversible manner, for instance as a function of the temperature.
In an advantageous embodiment the expandable medium expands as a function of the pH, wherein the reservoir is provided with electrodes. Using these electrodes the pH of the expandable medium is changed in coulometric manner.
In a subsequent embodiment the silicon chip is provided with dosing means for dosing an additive in the perfusion fluid respectively the dialysate.
These dosing means for instance comprise at least a second fluid channel which is provided at a first, closed outer end with electrodes and which debouches with a second, open outer end in a fluid channel.
Using the dosing means small quantities of fluid (for instance calibration fluid or reagents) can be dosed in accurate manner in very small quantities (in the order of nanolitres) into the first fluid channel in the silicon chip.
It is otherwise noted that the application of pumping means or dosing means according to the invention is not limited to systems for microdialysis. The dosing means are for instance particularly suitable for subcutaneous administration with a syringe of medication such as painkillers.
In an advantageous embodiment the inlet of the probe is also integrally received in the silicon chip.
In a preferred embodiment of a microdialysis device according to the invention, wherein the probe comprises two substantially concentric tubes, of which an inner tube comprises a portion protruding from a distal end of the outer tube, which portion is enclosed by a semi-permeable membrane connecting to the outer tube, wherein between the inner and the outer tube a through-flow channel is present, the silicon chip is provided with a first hole which extends in longitudinal direction and is formed successively by a first segment, a transition segment, a second segment and a third segment, wherein the inner periphery of the first segment corresponds with the outer periphery of said outer tube and the inner periphery of the second segment corresponds with the outer periphery of said inner tube, a second hole debouching in the transition segment and extending in substantially transverse direction and a third hole debouching in the third segment, wherein the outer tube is received with a proximal end portion in the first segment, and a portion of the inner tube protruding from the proximal end of the outer tube is received in the second segment in a manner such that the first hole is in communication with the through-flow channel between the inner and outer tube and the third hole is in communication with the interior of the inner tube.